An Orexin Antagonist for Insomnia: A Careful Look

Steven Dubovsky, MD

Positive results occurred at suvorexant doses higher than the ones approved by the FDA.

Orexin (hypocretin) is a neuromodulator that regulates wakefulness, and antagonists of its receptors, such as suvorexant, have been promising treatments for insomnia (NEJM JW Psychiatry Jun 11 2012). Two recent, randomized, placebo-controlled, 3-month, multicenter, registration trials of suvorexant dosing that were sponsored, conducted, and written by the manufacturer enrolled a total of 2030 participants with primary insomnia and no psychiatric or medical comorbidities (mean age, 56; ≥65, 41%).

At 40 mg for younger patients (ages, <65) and 30 mg for older ones, suvorexant was superior to placebo in improving several sleep measures. Subjective total sleep time (sTST) improved by about 30 minutes, and time to sleep onset by 10 minutes. On polysomnography, wakefulness after persistent sleep onset (WASO) and latency to persistent sleep at some points were statistically better. Low doses (patient ages: <65, 20 mg; ≥65, 15 mg) were superior to placebo in only one study and on two measures (TST throughout and WASO at month 3). The most common adverse effect was daytime somnolence at higher doses. Suvorexant did not produce narcolepsy symptoms, even though orexin neurotransmission is reduced in narcolepsy. Rebound insomnia occurred in some after withdrawal of the higher dose.

Citation(s):

Herring WJ et al. Suvorexant in patients with insomnia: Results from two 3-month randomized controlled clinical trials. Biol Psychiatry 2014 Oct 22; [e-pub ahead of print].